Substituted sulfonylacetamido cephalosporins

ABSTRACT

Cephalosporin compounds having various substituted sulfonylacetamido groups at position 7 have been prepared and have antibacterial activity.

This is a division of application Ser. No. 249,858 filed May 3, 1972,now U.S. Pat. No. 3,865,819.

This invention relates to cephalosporin compounds which haveantibacterial activity, in particular, compounds having a substitutedsulfonylacetamido substituent at position 7 of the cephem nucleus.

The compounds of this invention are represented by the followingstructure. ##SPC1##

Where:

X is lower alkyl of C₁ -C₆ ; phenyl, unsubstituted or substituted withnitro, amino, dialkylamino, each alkyl having C₁ -C₄, hydroxy, alkoxy(C₁ -C₄), or halogen; CF₃ ; NH₂ ; or mono or dialkylamino, each alkyl ofC₁ -C₄ ;

A is hydrogen, methyl, acetoxymethyl, pyridiniummethyl, CH₂ S--Het, CH₂SR, or CH₂ OR;

Het is a 5 or 6-membered heterocyclic ring containing one to four atomsselected from the group consisting of N, O and S, unsubstituted orsubstituted with from one to two groups selected from lower alkyl,cycloalkyl or alkenyl, each having one to four carbon atoms; loweralkoxy or alkoxyalkyl, each alkoxy or alkyl having one to four carbonatoms; hydroxy; CF₃ ; NHR; NR₂ ; SR; or halogen;

R is hydrogen or lower alkyl (C₁ -C₄); and

M is hydrogen, alkali metal cation, nontoxic ammonium cation, or when Ais pyridiniummethyl an anionic charge.

Cephalosporins with a wide variety of acyl groups at position 7 areknown in the prior art including substituted sulfinylalkanoyl groups.The present invention relates to substitutedsulfonylacetamidocephalosporins, having a doubled oxidized sulfur atom.

Preferred compounds are those where A is CH₂ S--Het and in particularwhere Het is tetrazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl,1,2,4-triazolyl, 1,2,3-triazolyl and the substituted derivativesthereof. Also preferred are compounds where X is methyl, ethyl, propyl,trifluoromethyl, phenyl, amino and dimethylamino.

The compounds of this invention are prepared by acylation of a7-aminocephalosporanic acid with the appropriately substitutedsulfonylacetic acid. The carboxyl group is activated prior or during theacylation reaction by one of the methods well known in the art. Theseinclude the mixed anhydride, acid halide and activated ester methods andthe use of a coupling reagent such as dicyclohexylcarbodiimide.

The alkyl and arylsulfonylacetic acids are prepared by oxidation of theappropriate substituted mercaptoacetic acid with an oxidizing agent; forexample, methylmercaptoacetic acid is oxidized with m-chloroperbenzoicacid to give methylsulfonylacetic acid. Alternatively the substitutedmercaptoacetic acid can be converted to an activated ester, such as theN-hydroxysuccinimide ester or the 2,4-dinitrophenyl ester, and thenoxidized to the activated sulfonylacetate. Aminosulfonylacetic acids(i.e., XSO₂ CH₂ COOH where X is amino or dialkylamino) are prepared fromcommercially available chlorosulfonylacetyl chloride by known methods(J. Amer. Chem. Soc., 81, 5655 (1959); British Pat. No. 1,067,965).

The 7-aminocephalosporins where A is CH₂ S--Het are prepared by knownmethods from 7-aminocephalosporanic acid (7-ACA) and the appropriateheterocyclic mercaptan compound. The compounds where A ispyridiniummethyl are prepared by acylation of 7-ACA and then reactionwith pyridine by known procedures. The compounds where A is hydrogen,methyl, alkylthiomethyl, or alkoxymethyl are prepared from materialsknown in the art, readily prepared by known methods or described herein.

The compounds of this invention have broad-spectrum antibacterialactivity with minimum inhibitory concentrations (MIC) ranging from 0.1to >200 ug/ml. Table 1 shows MIC's for a variety of compounds within thescope of this invention against various Gram-positive and Gram-negativebacteria.

                                      TABLE 1                                     __________________________________________________________________________    Compd.                                                                             S. aureus                                                                           S. aureus                                                                           S. villaluz                                                                          Strep.                                                                             Strep.                                                                              E. coli                                                                             E. coli                                                                             Kleb.                          No.* HH 127                                                                              SK 23390     pyog.                                                                              faecalis                                                                            SK 12140                                                                            HH 33779                                                                            pneumo.                                                C 203                                                                              HH 34358          SK 4200                        __________________________________________________________________________                                       MIC (μg/ml)                             54293                                                                              3.1   1.6          0.4  200    12.5 25     12.5                          55848                                                                              1.6   1.6          0.2  50     12.5 25    3.1                            57286                                                                              3.1   1.6          0.2  100   3.1    12.5 1.6                            57359                                                                              1.6   0.8          0.2  50    50    100    12.5                          57286                                                                              0.8   0.4          0.1  25    25    100   25                             59345                                                                              0.8   0.8   25     0.1  100   100   100   50                             59393                                                                              1.6   1.6   25     0.1  50    50    50    25                             59454                                                                              25    25    >200   0.4  >200  >200  >200  >200                           59586                                                                              1.6   0.8   100    0.2  100   6.3   25    3.1                            59623                                                                              100   0.8   100    0.1  100   25    50    6.3                            59641                                                                              0.4   0.4   100    0.1  25    3.1    12.5 1.6                            59758                                                                              3.1   1.6   50     0.1  200   6.3    12.5 6.3                            59857                                                                              1.6   1.6   25     0.2  100   25    50    6.3                            __________________________________________________________________________    Compd.                                                                              Kleb.  Pseudo. sp.                                                                           Salmonella                                                                            Shigella                                                                            Entero.                                                                             Serra.                                                                              Entero.                        No.*  pneumo.                                                                              HH 63   ATCC 12176                                                                            HH 112                                                                              aerog.                                                                              marc. cloaca                               SK 1200                      ATCH  ATCC  PaSL 969                                                          13048 13880                                __________________________________________________________________________    54293  12.5  >200     12.5   25    >200        >200                           55848 6.3    >200    3.1      12.5 >200        >200                           5726  3.1    >200    3.1     3.1   >200  >200  >200                           57359 6.3    >200     12.5   25    >200  >200  >200                           57360  12.5  >200    25      25    >200  >200  >200                           59345 100    >200    50      50    >200  >200  >200                           59393 25     >200     12.5   25     200  >200   200                           59454 > 200  >200    >200    >200  >200  >200  >200                           59586 3.1    >200    1.6      12.5  200  >200  >200                           59623 6.3    >200    3.1     25     200  >200                                 59641 1.6    >200    1.6     6.3    100  >200                                 59758 6.3    >200    3.1     0.1   >200  >200                                 59857 6.3    >200    3.1     25    >200  >200                                 __________________________________________________________________________     *See Table 2 for structures                                              

                  TABLE 2                                                         ______________________________________                                        Compound No.                                                                             X       A                                                          ______________________________________                                        54293      methyl  acetoxymethyl                                              55848      methyl  5-methyl-1,3,4-thiadiazol-2-                                                  ylthiomethyl                                               57286      methyl  1-methyltetrazol-5-ylthio-                                                    methyl                                                     57359      phenyl  acetoxymethyl                                              57360      phenyl  5-methyl-1,3,4-thiadiazol-2-                                                  ylthiomethyl                                               59345      methyl  pyridiniummethyl                                           59393      amino   acetoxymethyl                                              59454      methyl  methyl                                                     59586      methyl  5-methyl-1,2,4-triazol-3-                                                     ylthiomethyl                                               59623      ethyl   acetoxymethyl                                              59641      ethyl   5-methyl-1,3,4-thiadiazol-2-                                                  ylthiomethyl                                               59758      methyl  4-methyl-1,2,4-triazol-3-yl-                                                  thiomethyl                                                 59857      methyl  4-methyl-5-oxo-1,2,4-triazol-                                                 3-ylthiomethyl                                             ______________________________________                                    

These compounds are formulated and administered in the same manner asother cephalosporins with the dose depending on the subject and theinfection being treated.

The following examples illustrate the invention but are not to beconstrued as limiting the scope thereof.

EXAMPLE 1 7-Methylsulfonylacetamidocephalosporanic acid

Dicyclohexylcarbodiimide (20.6 g, 0.1 mol) was added to a solution ofmethylmercaptoacetic acid (10.7 g, 0.10 mol) and N-hydroxysuccinimide(11.5 g, 0.1 mol) in dry tetrahydrofuran (100 ml). The mixture wasstirred in an ice bath for one hour and then allowed to stand overnight.The precipitate was collected and the filtrate was evaporated to givethe crude product which was recrystallized from carbon tetrachloride.

The above activated ester (4.06 g, 0.02 mol) was dissolved in chloroform(40 ml) and the solution was cooled to 0°. To this was added over a 15minute period a solution of m-chloroperbenzoic acid (8.1 g, 0.04 mol) inether (50 ml). The reaction is stirred one hour in an ice bath and threedays at room temperature. The precipitated product was collected and wasrecrystallized from acetone to give the methylsulfonylacetate ester.

To a suspension of 7-ACA (1.64 g, 0.06 mol) in dry dimethylformamide (20ml) was added sufficient triethylamine to effect solution. The aboveester (1.4 g, 0.06 mol) was added to the solution at room temperaturewith stirring. After 1.25 hours the reaction was poured into ice waterand the aqueous mixture was acidified to pH 2 and extracted with ethylacetate. The extracts were dried and concentrated to a volume of about20 ml. An equal volume of ether was added followed by sodium2-ethylhexanoate and then more ether (100 ml.). The precipitate wascollected, washed with ether, and dried to yield the title compound asits sodium salt. The free acid is obtained by acidification of anaqueous solution of the sodium salt.

EXAMPLE 27-Methylsulfonylacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

To a suspension of7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid(1.09 g, 3 mmol) in dimethylformamide (25 ml) was added triethylamineuntil all the solid was dissolved. The activated methylsulfonylacetateester from Example 1 (0.705 g, 3 mmol) was added to the solution in oneportion. The reaction solution was stirred at room temperature for 5hours and then was added dropwise to ether (200 ml). The gummyprecipitate was stirred with filter aid and filtered. The filter cakewas washed with ether, and then stirred with acetonitrile (50 ml) andfiltered again. The filtrate was evaporated to a gummy residue which wasdissolved in water (40 ml). The aqueous phase was extracted with ethylacetate (40 ml), acidified to pH 2, and reextracted with ethyl acetate.The organic extracts of the acidic solution were washed with water,dried and concentrated to a volume of about 50 ml. Sodium2-ethylhexanoate in isopropanol was added to precipitate the sodium saltof the title compound. The free acid is obtained from the sodium salt bystandard methods.

EXAMPLE 37-Methylsulfonylacetamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

Triethylamine was added to a suspension of7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (1.72 g, 5 mmol) in dimethylformamide (25 ml) until a slightcloudiness remained. To this was added the activated sulfonyl ester fromExample 1 (1.18 g, 5 mmol) and the reaction was stirred at roomtemperature for 2 hours. The solution was poured into ice water (150 ml)and the resultant solution was extracted with ethyl acetate. The aqueousphase was acidified with 3N HCl to pH 2 and extracted with ethylacetate. The combined extracts were washed with water, dried andconcentrated to a volume of 50 ml. Sodium 2-ethylhexanoate was added andthen ether (200 ml). The precipitated sodium salt was collected, washedwith ether and dried. By standard methods, the free acid is obtainedfrom the sodium salt.

EXAMPLE 47-Phenylsulfonylacetamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

When phenylmercaptoacetic acid was reacted with N-hydroxysuccinimide andthen m-chloroperbenzoic acid according to the procedure in Example 1,N-hydroxysuccinimidyl phenylsulfonylacetate was obtained.

7-Amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (1.38 g, 0.04 mol) was suspended in dimethylformamide (25 ml) andtriethylamine was added until solution was effected. The above ester(1.1 g, 0.04 mol) was added and the reaction was stirred for 2 hours atroom temperature. The solution was added dropwise to ether (200 ml). Thesuspension was filtered through filter aid and the filter cake waswashed with ether. The product and filter aid were stirred with water(50 ml) for 20 minutes and refiltered. The aqueous filtrate wasextracted with ethyl acetate (which was discarded) and then acidified topH 1 with 3N HCl and reextracted with ethyl acetate. The extracts werewashed with water, dried, and sodium 2-ethylhexanoate was added. Thesodium salt was collected and dried. An aqueous solution of the sodiumsalt is adjusted to pH 2 and the free acid is collected.

EXAMPLE 5 7-Phenylsulfonylacetamidocephalosporanic acid

When the activated phenylsulfonylacetate of Example 4 was reacted with7-ACA according to the same procedure as Example 4, the title compoundwas obtained.

EXAMPLE 67-Trifluoromethylsulfonylacetamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

Trifluoromethylmethylsulfone (1.48 g, 0.01 mol) [W. E. Truce, et al., J.Amer. Chem. Soc., 74, 3594 (1952)] was dissolved in dry ether (50 ml)and the solution was cooled to -40°. A 2 molar solution of n-butyllithium (7.5 ml, 0.015 mol) was added; the reaction was warmed to ca.15°, stirred for 30 minutes, and then poured over crushed CO₂ withstirring. When the mixture reached room temperature it was shaken withwater (75 ml); the aqueous phase was separated, acidified to pH 1.5, andextracted with ether. The extracts were dried and evaporated to give anoil which crystallized on standing. The trifluoromethylsulfonylaceticacid was recrystallized from carbon tetrachloride.

Using the procedure in Example 1 trifluoromethylsulfonylacetic acid isesterified with N-hydroxysuccinimide and then is reacted with7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid using the procedure of Example 3 to give the title compound.

EXAMPLE 7 7-Trifluoromethylsulfonylacetamidocephalosporanic acid

The reaction of the activated ester of trifluoromethylsulfonylaceticacid from Example 6 with 7-ACA according to the procedure of Example 1gives the title compound.

EXAMPLE 8 7-Aminosulfonylacetamidocephalosporanic acid

Dicyclohexylcarbodiimide (1 g, 5 mmol) was added to a solution of 7-ACAt-butyl ester (1.65 g, 5 mmol) and aminosulfonylacetic acid (0.7 g, 5mmol) (British Pat. No. 1,067,965) in dry tetrahydrofuran (15 ml). Thesolution was stirred overnight at room temperature, filtered and theprecipitate was washed with tetrahydrofuran. Th filtrate and washingswere combined and evaporated to a gum. The gum was reacted withtrifluoroacetic acid (5 ml) for 15 minutes at room temperature and thenthe reaction solution was added dropwise to ether (150 ml). Theprecipitate was filtered, washed with ether, then stirred with ethylacetate and filtered. The filtrate was treated with sodium2-ethylhexanoate in isopropanol. The precipitated sodium salt wascollected, washed with ether and acetonitrile and dried. The sodium saltis converted to the free acid by standard methods.

EXAMPLE 97-Aminosulfonylacetamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

Using the procedure of Example 3,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid is reacted with N-hydroxysuccinimidyl aminosulfonylacetate(prepared in a similar manner as set forth in Example 1 fromaminosulfonylacetic acid and N-hydroxysuccinimide) to give the desiredproduct.

EXAMPLE 10

When an equivalent amount of a7-amino-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid listed belowis substituted in Example 2 for7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid,the appropriate7-methylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid is obtained.

7-Amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-n-butyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-dimethylamino-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-mercapto-1,3,4-thiadiazol-3-ylthiomethyl)-cephem-4-carboxylicacid

7-Amino-3-(3-methylthio-1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(3-methyl-1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(5-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(4,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(2,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(4-methyl-5-trifluoromethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(4-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(2-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(2-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(4-allyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-methoxymethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-cyclopropyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-bromo-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-hydroxy-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-hydroxy-4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(5-hydroxy-4-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(5-methyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-Amino-3-(4-pyrimidylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(2-pyrazinylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(3-pyridylthiomethyl)-3-cephem-4-carboxylic acid

7-Amino-3-(4-pyridylthiomethyl)-3-cephem-4-carboxylic acid

EXAMPLE 11

The reaction of7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acidor a 7-amino-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acidenumerated in Example 10 with activated phenylsulfonylacetate esteraccording to the procedure of Example 4 gives the appropriate7-phenylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid.

EXAMPLE 12

When the procedure of Example 6 is followed using7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acidor a 7-amino-3-heterocyclicthiomethylcephalosporin listed in Example 10,the corresponding7-trifluoromethylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid is obtained.

EXAMPLE 13

Substitution of7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acidor a cephalosporin compound listed in Example 10 in the procedure ofExample 9 gives the appropriate7-aminosulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid product.

EXAMPLE 147-Methylsulfonylacetamido-3-(1-pyridiniummethyl)-3-cephem-4-carboxylicacid

To a solution of 7-methylsulfonylacetamidocephalosporanic acid sodiumsalt (1.75 g, 4.0 mmol) in water (2 ml) was added potassium thiocyanate(7.87 g, 0.081 mol), water (2 ml) and pyridine (0.44 ml). The reactionwas heated at 65°-70° for 7 hours and then was cooled. The solution wasdiluted with water (75 ml) and the aqueous solution was chromatographedon a column of cross-linked polystyrene polymer (125 g of AmberliteXAD-2). The inorganic salts were eluted with water and then the productwas eluted with 95% ethanol. The ethanol fractions were evaporated togive the crude product which was dissolved in water filtered andlyophilized.

EXAMPLE 15

When trifluoromethylsulfonylacetamidocephalosporanic acid,aminosulfonylacetamidocephalosporanic acid, orphenylsulfonylacetamidocephalosporanic acid is substituted formethylsulfonylacetamidocephalosporanic acid in Example 14 thecorresponding 3-(1-pyridiniummethyl)cephalosporin is obtained.

EXAMPLE 167-(N,N-Dimethylaminosulfonylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-yl)-3-cephem-4-carboxylicacid

N,N-Dimethylaminosulfonylacetic acid is prepared in an analogous methodas aminosulfonylacetic acid and then is reacted with7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid according to the procedure of Example 9 to give the title compound.

EXAMPLE 17

When 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid or a 7-amino-3-heterocyclic cephalosporin enumerated in Example 10is reacted with N,N-dimethylaminosulfonylacetic acid by the procedure ofExample 16 the corresponding7-(N,N-dimethylaminosulfonylacetamido)-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid is obtained.

EXAMPLE 18

The reaction of N,N-dimethylaminosulfonylacetic acid with 7-ACA t-butylester according to the procedure of Example 8 gives7-(N,N-dimethylaminosulfonylacetamido) cephalosporanic acid.

When the above product is reacted with pyridine using the procedure ofExample 14,7-(N,N-dimethylaminosulfonylacetamido)-3-(1-pyridiniummethyl)-3-cephem-4-carboxylicacid is obtained.

EXAMPLE 19 7-Methylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid

7-Amino-3-methyl-3-cephem-4-carboxylic acid (7-ADCA) (2.14 g, 0.01 mol)was suspended in dry dimethylformamide (30 ml) and1,5-diazobicyclo[4.3.0]non-5-ene was added until only a slightcloudiness remained. The activated ester from Example 1 (2.35 g, 0.01mol) was added and the reaction was stirred for 2.5 hours at roomtemperature. The solution was filtered into ether (300 ml) and then thefiltrate was filtered through filter acid. The filter cake was stirredwith water (50 ml) and refiltered. The filtrate was acidified to pH 1.5with 3N HCl and extracted with ethyl acetate. The organic extracts werewashed with water, dried, and concentrated to ca. 50 ml. Sodium2-ethylhexanoate was added and the precipitated sodium salt wascollected, washed with ethyl acetate and dried. The free acid isobtained from the sodium salt by standard methods.

EXAMPLE 20

When the activated esters of phenylsulfonylacetic acid,trifluoromethylsulfonylacetic acid, aminosulfonylacetic acid, orN,N-dimethylaminosulfonylacetic acid are reacted with 7-ADCA accordingto the procedure in Example 19 the corresponding7-sulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid is obtained.

EXAMPLE 21 7-Ethylsulfonylacetamidocephalosporanic acid

N-hydroxysuccinimidyl ethylsulfonylacetate was prepared fromethylmercaptoacetic acid according to the procedure of Example 1. To asuspension of 7-ACA (2.18 g, 8 mmol) in dry dimethylformamide (50 ml)was added triethylamine until solution was effected and then theactivated ester (1.99 g, 8 mmol) was added in one portion. The resultantreaction mixture was stirred 1.5 hours at room temperature and thenpoured with stirring into ether (400 ml) which caused a gummy residue toprecipitate. The mixture was filtered through Celite and the filter cakewas stirred with water (100 ml) until the residue was dissolved. Theaqueous solution was filtered, washed with ethyl acetate, covered withfresh ethyl acetate and acidified with 3N HCl to pH 2. The acidicsolution was extracted with ethyl acetate. The combined extracts werewashed with water, dried, and evaporated to give the title compound.

EXAMPLE 227-Ethylsulfonylacetamido-3-(2-methyl-1,3,5-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

Using the activated 7-ethylsulfonylacetate ester (1.99 g, 8 mmol) and7-amino-3-(2-methyl-1,3,5-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (2.75 g, 8 mmol) in the procedure of Example 21, the title compoundwas prepared.

EXAMPLE 23

When 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid or any of the compounds enumerated in Example 10 are substitutedfor 7-ACA in the procedure of Example 21 the corresponding7-ethylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid is obtained.

Similarly, 7-ethylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acidis obtained by acylating 7-ADCA using the procedure of Example 21.

EXAMPLE 24

Propylmercaptoacetic acid is converted into N-hydroxysuccinimidylpropylsulfonylacetate in the same manner as the methyl analog inExample 1. This ester is reacted with 7-ACA, 7-ADCA,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid, 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid, or any of the compounds enumerated in Example 10 according to theprocedure of Example 21 to give the appropriate7-propylsulfonylacetamidocephalosporin.

EXAMPLE 25

Acylation of 7-amino-3-methylthiomethyl-3-cephem-4-carboxylic acid(Belgian Patent No. 743,754) with the activated esters ofmethylsulfonylacetic acid, ethylsulfonylacetic acid, orpropylsulfonylacetic acid according to the procedure of Example 1 givesthe corresponding7-alkylsulfonylacetamido-3-methylthiomethyl-3-cephem-4-carboxylic acid.Using the procedure of Example 8 the above cephem nucleus is acylatedwith dimethylaminosulfonylacetic acid to give7-dimethylaminosulfonylacetamido-3-methylthiomethyl-3-cephem-4-carboxylicacid.

EXAMPLE 26

Using the procedure of Example 1,7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid [J. Med. Chem., 14,113(1971)] is acylated with the activated ester of methylsulfonylaceticacid, ethylsulfonylacetic acid, or propylsulfonylacetic acid to give thecorresponding7-alkylsulfonylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid. Thesame cephem nucleus is acylated with dimethylaminosulfonylacetic acid bythe procedure of Example 8 to give7-dimethylaminosulfonylacetamido-3-methoxymethyl-3-cephem-4-carboxylicacid.

EXAMPLE 27 3-Formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid

7-(2-Thienylacetamido)cephalosporanic acid (45 g, 0.11 mol) wasdissolved in dry pyridine (135 ml) by warming. This solution was cooledin an ice bath and acetic anhydride (13.5 ml) was added with stirring.After stirring 0.5 hour the reaction was stored in a refrigerator 18hours during which time the mixture solidified. Ether was added to themixture and the solid pyridine salt was collected and washed with ether.The salt was suspended in ethyl acetate (400 ml) with stirring and wascollected again. The salt was then dissolved in a mixture of water (300ml), ethyl acetate (400 ml) and 2N HCl (54 ml); the aqueous phase wassaturated with NaCl and then was separated. The organic phase was washedwith saturated NaCl solution, filtered through coarse filter paper threetimes, and evaporated to yield the Δ² -isomer (32.4 g).

The Δ² -isomer (32.4 g) was suspended in a mixture of acetone (60 ml)and water (300 ml) and 5% Na₂ CO₃ solution was added until pH 10.5 wasreached. The solution was allowed to stand two days during which timeadditional 5% Na₂ CO₃ was added several times to maintain the solutionat pH 10.5. The reaction was cooled in ice, layered with ethyl acetateand acidified with 6N H₂ SO₄ to pH 1.8. The aqueous phase was saturatedwith NaCl and separated. The organic phase was washed with saturatedNaCl solution, filtered through coarse filter paper and evaporated togive the product, the Δ² -3-hydroxymethyl compound (17.4 g).

A solution of the above product (17.4 g, 0.049 mol) in acetone (850 ml)was cooled to -10° and then Jones reagent [chromic trioxide (26.72 g)dissolved in concentrated H₂ SO₄ (23 ml) and then diluted to 100 ml withwater] was added dropwise until the brown color persisted. Excess Jonesreagent was decomposed with isopropanol, the green reaction mixture wasfiltered and the green precipitate was washed with acetone. The combinedfiltrate and washings were diluted with water (200 ml) and ethyl acetate(400 ml) and then saturated with NaCl. The organic phase was separated,washed with saturated NaCl solution and dried over MgSO₄. Evaporation ofthe solvent gave the crude product which was triturated with methanol togive the product as its methanoate (8.4 g). This product was dissolvedin ethyl acetate (2000 ml) and then evaporated in vacuo to give thetitle compound (7.8 g).

EXAMPLE 28 Benzhydryl3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate

A solution of diphenyldiazomethane (0.213 g, 1.1 mmol) in drytetrahydrofuran (2 ml) was added dropwise with stirring to the3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (0.352 g., 1mmol) in dry tetrahydrofuran (10 ml) at 40°. The reagent was allowed tocompletely react as noted by the color changes between each addition.The reaction was stirred at 40° for 2 hours after the addition wascompleted and then the solvent was removed in vacuo. The residual oilwas dissolved in chloroform, washed with 5% NaHCO₃, dried over MgSO₄ andconcentrated to half volume. The product was precipitated by theaddition of hexane.

EXAMPLE 29 Benzhydryl-7-(2-thienylacetamido)-3-cephem-4-carboxylate

A mixture of the benzhydryl ester from Example 28 (2.5 g, 4.79 mmol)tris-(triphenylphosphine)chlororhodium (3.5 g. 4.79 mmol) and drytoluene (75 ml) was refluxed under nitrogen for 5.5 hours. The reactionmixture was cooled, the rhodium complex was removed by filtration andthe filtrate was poured slowly into petroleum ether (250 ml) withstirring. The precipitated solid, which was a mixture of rhodium complexand product, was collected. The product was purified by chromatographyon a silica gel column (250 g) using 99:0.5 chloroform:ethyl acetate aseluent. Fractions of 4.5 ml were collected; fractions 1-47 discarded,48-66 contained bis-(triphenylphosphine)carbonylchlororhodium, and67-198 contained the product. NMR data indicated the product afterchromatography to be the Δ³ isomer instead of the Δ ² isomer. Adecoupling experiment showed the 2-methylene group at 3.3 ppm. to becoupled with the 3-proton at 6.6 ppm.

EXAMPLE 30 Benzhydryl 7-amino-3-cephem-4 -carboxylate

Benzhydryl 7-(2-thienylacetamido)-3-cephem-4-carboxylate (2.45 g. 5mmol) was dissolved in calcium hydride dried benzene (130 ml) containingdry pyridine (0.59 g, 7.4 mmol). The solution was maintained at 0° andPCl₅ (1.54 g. 7.4 mmol.) was added with stirring. The reaction mixturewas stirred under nitrogen at 0° for 3 hours and then the solvent wasremoved in vacuo. Anhydrous methanol (260 ml) was added to the residueand the resultant mixture was allowed to stand two hours. The methanolwas removed in vacuo and the residue was treated with 20% aqueoustetrahydrofuran. After 15 minutes the tetrahydrofuran was removed invacuo and the aqueous residue was adjusted to pH 7.5 and extracted withethyl acetate. The extracts were washed with water, dried over MgSO₄ andevaporated to give the solid product which was triturated withchloroform-petroleum ether and dried under high vacuum.

EXAMPLE 31 7-Methylsulfonylacetamido-3-cephem-4-carboxylic acid

A solution of benzhydryl 7-amino-3-cephem-4-carboxylate (0.78 g, 2mmol), methylsulfonylacetic acid (0.27 g, 2 mmol), anddicyclohexylcarbodiimide (0.4 g, 2 mmol) in dry tetrahydrofuran (15 ml)is stirred at room temperature overnight. The precipitate is collectedand washed with tetrahydrofuran and the combined filtrate and washingsare evaporated in vacuo. The residue is treated with a cold soluton oftrifluoroacetic acid (10 ml) and anisole (0.5 g) for 15 minutes and thenconcentrated in vacuo. The residue is dissolved in ethyl acetate andtreated with 5% NaHCO₃. The aqueous phase is adjusted to pH 2 and theprecipitated product is collected and dried.

EXAMPLE 32

When ethylsulfonylacetic acid, propylsulfonylacetic acid,trifluoromethylsulfonylacetic acid, phenylsulfonylacetic acid,aminosulfonylacetic acid, or N,N-dimethylaminosulfonylacetic acid issubstituted for methylsulfonylacetic acid in the procedure of Example31. The corresponding 7-sulfonylacetamido-3-cephem-4-carboxylic acid isobtained.

EXAMPLE 33

An injectable pharmaceutical composition is formed by adding sterilewater or sterile saline solution (2 ml) to 500 mg of sodium7-methylsulfonylacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate.

Pharmaceutical compositions of the other antibacterial compoundsdisclosed above may be formulated in a similar manner.

It is recognized that when the substituent on the heterocyclic group ishydroxy or mercapto that it is possible for the substituent to exist inanother tautomeric form. i.e. the oxo or thiono form. The compounds mayexist exclusively as one of the two tautomers or may be in equilibriumbetween the two; however, these are all included within the scope ofthis invention.

What we claim is:
 1. A compound of the structure: ##SPC2##where: X is NH₂, or mono or dialkylamino, each alkyl from C₁ -C₄ ; A is CH₂ S-Het; Het is tetrazolyl, thiadiazolyl, triazolyl, oxadiazolyl, pyrimidyl, pyrazinyl or pyridyl, unsubstituted or substituted with one or two groups selected from the group consisting of lower alkyl, cycloalkyl, or alkenyl, each having one to four carbon atoms; lower alkoxy or alkoxyalkyl, each alkyl or alkoxy having one to four carbon atoms; hydroxy; CF₃ ; NHR; NR₂ ; SR; or bromine; R is hydrogen or lower alkyl (C₁ -C₄); and M is hydrogen, alkali metal cation, or nontoxic ammonium cation.
 2. A compound as claimed in claim 1 where X is NH₂ or N(CH₃)₂.
 3. A compound as claimed in claim 2 where Het is tetrazol-5-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-5-yl or 1,3,4-oxadiazol-5-yl, each Het group being unsubstituted or substituted with hydroxy or one or two lower alkyl groups.
 4. A compound as claimed in claim 1 being the compound 7-aminosulfonylacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
 5. A compound as claimed in claim 1 being the compound 7-aminosulfonylacetamido-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid.
 6. A compound as claimed in claim 1 being the compound 7-(N,N-dimethylaminosulfonylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
 7. A compound as claimed in claim 1 being the compound 7-(N,N-dimethylaminosulfonylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. 